Plasma proteome profiling reveals differentially expressed lipopolysaccharide-binding protein among leptospirosis patients

Fish-Low, Cheng-Yee; Than, Leslie Thian Lung; Ling, King-Hwa; Lin, Qingsong

doi:10.1016/j.jmii.2018.12.015

Cited by 10 publications

(11 citation statements)

References 36 publications

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“…Interestingly, in the case of L . interrogans , LBP was shown to be the only serum factor upregulated in the blood of patients upon infection [ 61 ]. Therefore, we cannot exclude that LBP contributes to the effect.…”

Section: Discussionmentioning

confidence: 99%

“…Just like CD14, LBP plays an important role in the CD14-dependent endocytosis of TLR4 [19] and plays a crucial role in the signaling of low doses of LPS via MyD88 [60]. Interestingly, in the case of L. interrogans, LBP was shown to be the only serum factor upregulated in the blood of patients upon infection [61]. Therefore, we cannot exclude that LBP contributes to the effect.…”

Section: Plos Pathogensmentioning

confidence: 96%

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Leptospiral LPS escapes mouse TLR4 internalization and TRIF‑associated antimicrobial responses through O antigen and associated lipoproteins

et al. 2020

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Leptospirosis is a worldwide re-emerging zoonosis caused by pathogenic Leptospira spp. All vertebrate species can be infected; humans are sensitive hosts whereas other species, such as rodents, may become long-term renal carrier reservoirs. Upon infection, innate immune responses are initiated by recognition of Microbial Associated Molecular Patterns (MAMPs) by Pattern Recognition Receptors (PRRs). Among MAMPs, the lipopolysaccharide (LPS) is recognized by the Toll-Like-Receptor 4 (TLR4) and activates both the MyD88dependent pathway at the plasma membrane and the TRIF-dependent pathway after TLR4 internalization. We previously showed that leptospiral LPS is not recognized by the human-TLR4, whereas it signals through mouse-TLR4 (mTLR4), which mediates mouse resistance to acute leptospirosis. However, although resistant, mice are known to be chronically infected by leptospires. Interestingly, the leptospiral LPS has low endotoxicity in mouse cells and is an agonist of TLR2, the sensor for bacterial lipoproteins. Here, we investigated the signaling properties of the leptospiral LPS in mouse macrophages. Using confocal microscopy and flow cytometry, we showed that the LPS of L. interrogans did not induce internalization of mTLR4, unlike the LPS of Escherichia coli. Consequently, the LPS failed to induce the production of the TRIF-dependent nitric oxide and RANTES, both important antimicrobial responses. Using shorter LPS and LPS devoid of TLR2 activity, we further found this mTLR4-TRIF escape to be dependent on both the co-purifying lipoproteins and the fulllength O antigen. Furthermore, our data suggest that the O antigen could alter the binding of the leptospiral LPS to the co-receptor CD14 that is essential for TLR4-TRIF activation. Overall, we describe here a novel leptospiral immune escape mechanism from mouse macrophages and hypothesize that the LPS altered signaling could contribute to the stealthiness and chronicity of the leptospires in mice.

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Section: Discussionmentioning

confidence: 99%

Section: Plos Pathogensmentioning

confidence: 96%

Leptospiral LPS escapes mouse TLR4 internalization and TRIF‑associated antimicrobial responses through O antigen and associated lipoproteins

et al. 2020

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“…A study using complex mixtures of mouse neuro2A cells demonstrated that emPAI was strongly correlated with the actual protein amount in a wide dynamic range from 30 fmol/μL to 1.8 pmol/μL in the sample solution [ 7 ]. Nevertheless, this method is more suitable for interprotein and intrasample quantification with its intersample performance showing little evidence [ 13 – 16 ]. Shinoda et al used emPAI% to calculate the molecular percentage of all the identified proteins for fractionated samples in a large-scale LC-MS/MS analysis [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

“…intrasample quantification with its intersample performance showing little evidence [13][14][15][16]. Shinoda et al used emPAI% to calculate the molecular percentage of all the identified proteins for fractionated samples in a large-scale LC-MS/MS analysis [8].…”

Section: Plos Onementioning

confidence: 99%

Plasma proteome atlas for differentiating tumor stage and post-surgical prognosis of hepatocellular carcinoma and cholangiocarcinoma

Chang

2020

PLoS ONE

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Although mass spectrometry-based plasma proteomics enables sensitive and large-scale discovery and validation of biomarkers for various diseases, its integrative application to hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) is not well investigated. Therefore, we analyzed albumin-and immunoglobulin G-depleted plasma samples from 148 and 60 patients with HCC and CCA, respectively, using liquid chromatography-tandem mass spectrometry. The algorithm used to measure the content of each protein was the percentage of exponentially modified protein abundance index. From 5320 proteins assayed in plasma, 53 and 25 biomarker candidates were identified for HCC and CCA, respectively. The abundance of six and two HCC markers particularly protruded in stage II and III, respectively, whereas plasma serine protease inhibitor was the sole marker the level of which steadily decreased with CCA progression. From a prognostic facet, we showed candidate markers and their cutoff levels for evaluating probability of tumor recurrence and patient survival period. Combination Kaplan-Meier models showed that HCC stage III or IV and both the content of alpha-2-HS-glycoprotein and apolipoprotein CIII <0.2% exhibited the poorest post-surgical recurrence-free and overall survivals. Furthermore, the content of afamin �0.2% played a significant role on the poor prognosis in patients with CCA. Our findings, taken together, characterized novel plasma biomarker signatures in dissecting tumor stages and post-surgical outcomes of HCC and CCA.

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“…Just like CD14, LBP plays an important role in the CD14-dependent endocytosis of TLR4 [20] and plays a crucial role in the signaling of low doses of LPS via MyD88 [62]. Interestingly, in the case of L. interrogans , LBP was shown to be the only serum factor upregulated in the blood of patients upon infection [63]. Therefore, we cannot exclude that LBP contributes to the effect.…”

Section: Discussionmentioning

confidence: 99%

Leptospiral LPS escapes mouse TLR4 internalization and TRIF-associated antimicrobial responses through O antigen and associated lipoproteins

Bonhomme

Santecchia

Vernel-Pauillac

et al. 2020

Preprint

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16 Leptospirosis is a worldwide re-emerging zoonosis caused by pathogenic Leptospira spp. All 17 vertebrate species can be infected; humans are sensitive hosts whereas other species, such as rodents, 18 may become long-term renal carrier reservoirs. Upon infection, innate immune responses are initiated 19 by recognition of Microbial Associated Molecular Patterns (MAMPs) by Pattern Recognition 20Receptors (PRRs). Among MAMPs, the lipopolysaccharide (LPS) is recognized by the 21 Toll-Like-Receptor 4 (TLR4) and activates both the MyD88-dependent pathway at the plasma 22 membrane and the TRIF-dependent pathway after TLR4 internalization. We previously showed that 23 leptospiral LPS is not recognized by the human TLR4, whereas it signals through murine TLR4, 24 which mediates mouse resistance to acute leptospirosis. However, leptospiral LPS has low 25 endotoxicity in mouse cells and is an agonist of TLR2, the sensor for bacterial lipoproteins. Here, 26 using confocal microscopy and flow cytometry, we showed that the LPS of L. interrogans did not 27 induce internalization of TLR4 in mouse macrophages, unlike the LPS of Escherichia coli. 28Consequently, the LPS failed to induce the production of the TRIF-dependent nitric oxide and 29 RANTES, both important antimicrobial responses. Using shorter O antigen LPS and repurified 30 leptospiral LPS with reporter HEK cells, we further found this TLR4-TRIF escape to be dependent on 31 both the co-purifying lipoproteins and the full-length O antigen. Furthermore, our data suggest that the 32 O antigen could alter the binding of the leptospiral LPS to the co-receptor CD14 that is essential for 33 TLR4-TRIF activation. Overall, we describe here a novel immune escape mechanism linked to 34 leptospiral LPS. We hypothesize that the LPS, already known as a virulence factor, plays a major role 35 in the innate immune evasion of the leptospires, thereby contributing to their stealthiness and 36 chronicity in mice. Author summary 38Leptospira interrogans is a bacterial pathogen, responsible for leptospirosis, a worldwide neglected 39 reemerging disease. L. interrogans may cause an acute severe disease in humans, whereas rodents and 40 other animals asymptomatically carry the leptospires in their kidneys. They can therefore excrete live 41 bacteria in urine and contaminate the environment. Leptospires are stealth pathogens known to escape 42 the innate immune defenses of their hosts. They are covered in lipopolysaccharide (LPS), a bacterial 43 motif recognized in mammals through the Toll-like receptor 4 (TLR4), which triggers two different 44 signaling pathways. We showed previously that pathogenic leptospires escape TLR4 recognition in 45 humans. Here we show in mice that the leptospiral LPS triggers only one arm of the TLR4 pathway 46 and escapes the other, hence avoiding production of antimicrobial compounds. Removing the 47 lipoproteins that always co-purify with the leptospiral LPS, or using shorter LPS, restores the 48 stimulation of both pathways. This suggests a novel escape mechan...

show abstract

Plasma proteome profiling reveals differentially expressed lipopolysaccharide-binding protein among leptospirosis patients

Cited by 10 publications

References 36 publications

Leptospiral LPS escapes mouse TLR4 internalization and TRIF‑associated antimicrobial responses through O antigen and associated lipoproteins

Leptospiral LPS escapes mouse TLR4 internalization and TRIF‑associated antimicrobial responses through O antigen and associated lipoproteins

Plasma proteome atlas for differentiating tumor stage and post-surgical prognosis of hepatocellular carcinoma and cholangiocarcinoma

Leptospiral LPS escapes mouse TLR4 internalization and TRIF-associated antimicrobial responses through O antigen and associated lipoproteins

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